Analgesic compositions and methods containing 2-cyclohexen-1-ylamine or 3-cyclohexen-1-ylamine



nited US. Cl. 424325 Claims ABSTRACT OF THE DISCLOSURE Therapeutical compositions containing 2-cyclohexen-1- ylamine and/or 3-cyclohexen-1-ylamine and/or at least one pharmaceutically acceptable acid addition salt thereof in combination with a pharmaceutical carrier, and a method for the treatment of pain comprising the administration of said compositions to mammals requiring such treatment.

DETAILED DISCLOSURE This invention relates to a method for therapeutic treatment and to compositions useful for this purpose.

More particularly the invention pertains to a method for the treatment of pain in mammals involving the administration to said mammals of an effective amount of at least one compound selected from the group consisting of 2-cyclohexen-1-ylamine, 3-cyclohexen-1-ylamine and the pharmaceutically acceptable acid addition salts thereof, which compounds were not hitherto suggested for that purpose, in combination with a pharmaceutical carrier. It is also an object of the invention to provide therapeutic compositions consisting essentially of (l) at least one of the compounds of the aforementioned group and (2) a pharmaceutical carrier.

The cyclohexenylamines of this invention as well as their acid addition salts have been found to unexpectedly exhibit analgesic action together with a very favorable therapeutic index. The analgesic action of these compounds may illustratively be demonstrated, for instance, by means of the test described by E. Siegmund, R. Cadmus, and G. Lu, Proc. Soc. Exp. Biol. Med. 95, 729 (1957), and/or the test described by H. Friebel and A. Reichle, Arch. Exper. Path. und Pharmakol. 226, 551 (1955).

In the test described by E. Siegmund et al., better known as writhing test, the amount of substance necessary to inhibit the pain-stretch syndrome caused by intraperitoneal injection of Z-phenyl-1,4-benzoquinone in the mouse is determined. On oral administration, the LD (effective dosage in 60% of mice) is, e.g.:

For- Mg./kg. 2-cyclohexen-1-ylamine hydrochloride 60' Z-cyclohexen-l-ylamine salicylate 79 3-cyclohexen-l-ylamine hydrochloride 50 3-cyclohexen-l-ylamine salicylate 70 Also effective both on oral as well as parenteral administration are the above mentioned salts in the second test described by H. Priebel et al. In this test pain is induced by heat in the mouse tail, prior to and after the administration of the test compound, and the respective time is measured from the moment when the heat reaches the mouse tail till the moment at which the mouse twitches its tail, thus enabling determination of the intensity and duration of the analgesic efifect of the test compound atent {I administered. The average dosage on oral administration causing in this test a 50% increase in the threshold of irritation for 60 minutes is, e.g.:

In comparison thereto, the acute toxicity (LD for, e.g., 3-cyclohexen-1-ylamine hydrochloride, is:

Mg./ kg. per os Mouse 1195 Rat 1350 Rabbit 615 Guinea pig 965 These favorable pharmacological properties render the cyclohexenylamines of this invention, particularly in the form of their pharmaceutically acceptable acid addition salts, suitable as active substances for analgesics i.e. therapeutical compositions consisting essentially of active ingredient and pharmaceutical carrier, which are useful for the treatment, amelioation and relief, of pain of various origin in mammals.

The effective amount of active ingredient which consists of at least one of the above mentioned cyclohexenylamines and/or at least one of the acid addition salts thereof, that is to be administered to a mammal depends on the species, age, weight, subject, the particular condition to be treated and the mode of administration. For instance, on oral or rectal administration of dosage units of the therapeutic compositions according to the invention generally daily dosages of about 100 mg. to 800 mg. of active ingredient are given, whereas on parenteral administration the daily dosages are generally between about 20 mg. and 200 mg. of active ingredient.

As mentioned above the therapeutic compositions according to the invention contain at least one of the cyclohexenylamines, supra, and/or at least one pharmaceutically acceptable addition salt thereof with an inorganic or organic acid, combined with an inert carrier and, if desired, further additives. These compositions are presented for oral, parenteral or rectal administration to mammals in solid and liquid dosage units, such as tablets, dragees (sugar coated tablets), capsules, suppositories, rectal capsules, ampoules, and the like, and for local or percutaneous application to mammals in forms not made up into single dosages, such as ointments, tinctures and other solutions, containing suitable quantities of the active substances of the invention.

Suitable dosage units for the oral or rectal administration such as dragees (sugar coated tablets), tablets, capsules or suppositories, preferably contain 25-200 mg. of at least one of the cyclohexenylamines mentioned and/ or at least one pharmaceutically acceptable acid addition salt thereof. In these dosage units the amount of active ingredient is preferably 5% to To produce tablets or dragee cores, the active substances are combined with, e.g. solid pulverulent carriers such as lactose, saccharose, sorbitol or mannitol; starches such as potato starch, maize starch or amylopectin, also laminaria powder or citrus pulp powder; cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols of suitable molecular weights, to form tablets or dragee cores. The latter are coated, e.g. with concentrated sugar solutions which can also contain, e.g. gum ara-bic, talcum and/or titanium dioxide, or with a lacquer dissolved in easily volatile organic solvents or mixtures of solvents. Dyestuffs can be added to these coatings, e.g. to distinguish between different dosages of active substance.

Other suitable oral dosage units are hard gelatine cap sules as well as soft, closed capsules made from gelatine and a softener such as glycerol. The former contain the active substance and the carrier, preferably as a granulate, in admixture with lubricants such as talcum or magnesium stearate and, optionally, stabilisers such as sodium meta bisulphite (Na S O or ascorbic acid. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquid carriers such as liquid polyethylene glycols; stabilisers can also be added.

Examples of dosage units for rectal administration are suppositories which consist of a combination of at least one of the cyclohexenylamines mentioned and/ or at least one suitable salt thereof using as a carrier suppository foundation, or also gelatine rectal capsules which contain a combination of at least one of the above substances with polyethylene glycols of suitable molecular weight as carriers.

Ampoules for parenteral, particularly intramuscular and also intravenous administration, preferably contain 100 mg. of active ingredient selected from the pharmaceutically acceptable, water soluble acid addition salts of the cyclohexenylamines mentioned, the carrier being Water. The concentration of the active ingredient is preferably between 0.5% and 10%. If necessary, suitable stabilising agents and/or buffer substances are added to the ampoule solutions.

Analgesics in forms not made up into single dosages such as ointments, tinctures and other solutions for local or percutaneous application are prepared with the aid of the usual ointment foundations or pharmaceutically acceptable solvents as carriers.

The analgesically active cyclohexenylamines of the invention are known and may be prepared by known methods as, for example, described by F. Hofmann and P. Damm in Chemisches Zentralblatt, 1926. I. 2342 if, and by M. Hanack and W. Keberle in Chemische Berichte 96, 2937 if. (1963).

As already indicated, in addition to the cyclohexenylamines as free bases the salts thereof, particularly their addition salts with e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methane sulfonic acid, ethane sulfonic acid, 2-hydroxyethane sulfonic acid, (Z-cyclohexen 1 ylamino)-methane sulfonic acid, (3- cyclohexen-l-ylamino)-methane sulfonic acid, acetic acid lactic acid, succinic acid, fumaric acid, maleic acid, malic acid, tartaric acid, citric acid, ascorbic acid, benzoic acid, salicylic acid, phenylacetic acid, mandelic acid, embonic acid or 1,5-naphthalene disulfonic acid, are used as analgesically active substances according to the invention.

Those mentioned and other addition salts can be produced in the usual way. For example, the acid desired as salt component or a solution thereof is added to a solution, optionally warmer, of 2-cyclohexen-l-ylamine or 3- cyclohexen-l-ylamine in water or in an organic solvent such as methanol, ethanol, isopropanol, acetone, butanone or diethyl ether, and the salt which is precipitated immediately or after cooling, concentrating or adding a second organic liquid, e.g. diethyl ether, to one of the alkanols mentioned, is separated.

Examples for the production of some salts which have not hitherto been described as well as of a number of representative dosage units are given below. The temperatures in these examples are given in degrees centigrade.

Example 1 97.0 g. of 3-cyclohexen-1-ylamine dissolved in 300 ml. of isopropanol are neutralised by the addition dropwise of 167 ml. of 6 N hydrochloric acid While stirring and cooling and then the whole is concentrated under 20 torr. The crystalline residue is dissolved in 120-150 ml. of hot isopropanol and allowed to slowly crystallise. Finally the crystal slurry is cooled in ice and then filtered under suction. In this way 3-cyclohexen-1-ylamine hydrochloride is Obtained, M.P. 181l82.

Example 2 9.7 g. of 3-cyclohexen-l-ylamine are dissolved in 30 ml. of isopropanol and the solution is poured all at once into a vigorously stirred, fine suspension of 19.1 g. of (3-cyclohexen-1-ylamino)-methane sulfonic acid in 200 ml. of isopropanol. The reaction mixture is then heated to 3540 whereupon, to all intents and purposes, a solution is obtained. Any undissolved parts are quickly filtered off under suction. On cooling, the salt of 3-cyclohexen-1- ylamine with (3-cyclohexen-l-ylamino)-methane sulfonic acid crystallises out, M.P. 126-128".

Example 3 (a) A solution of 5.8 g. of maleic acid in ml. of isopropanol is added dropwise to a stirred and cooled solution of 5.0 g. of 3-cyclohexen-1-ylamine in a mixture of 25 ml. of ether and 25 ml. of isopropanol. Precipitation of the salt is completed by the addition of ml. of ether. The precipitate is filtered off under suction. After recrystallisation from methanol, the 3-cyclohexen-l-ylamine maleate melts at 133-135".

(b) 3-cyclohexen-1-ylamine methane sulfonate, M.P. 165-168 (from isopropanol), is obtained analogously from 5 .0 g. of cyclohexen-l-ylamine and 4.8 g. of methane sulfonic acid.

(0) 3-cyclohexen-1-ylamine salicylate, M.P. 104-106" (from acetone/ether) is obtained analogously from 5.0 g. of 3-cyclohexen-l-ylamine and 6.9 g. of salicyclic acid.

(d) 2-cyclohexen-l-ylamine salicylate, M.P. 132134 (from butanone/isopropanol) is obtained analogously from 5 .0 g. of 2-cyclohexene-l-ylamine and 6.9 g. of salicyclic acid.

(e) 2-cyclohexen-l-ylarnine hydrochloride, M.P. 161 (from abs. ethanol) is obtained analogously from 24.7 g. of 2-cyclohexen-1-ylamine in 100 m1. of isopropanol by neutralisation with 90 ml. of 2.8 N etheral hydrochloric acid.

The following examples for the production of tablets, dr-agees, capsules, suppositories and ampoules further illustrate but in no way limit the scope of the invention.

Example 4 500.0 g. of active substance, e.g. 3-cyclohexene-1-ylamine hydrochloride or 2-cyclohexen-1-ylamine hydrochloride are mixed with 550.0 g. of lactose and 292.0 g. of potato starch. The mixture is moistened with an alcoholic solution of 8.0 g. of gelatine and granulated through a sieve. After drying, 60.0 g. of potato starch, 60.0 g. of talcum, 10.0 g. of magnesium stearate and 20.0 g. of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets each weighing 150 mg. and containing 50 mg. of active substance. If desired, the tablets can be grooved for better adaptation of the dosage.

Example 5 A granulate is prepared from 250.0 g. of active sub stance, e.g. 3-cyclohexen-1-ylamine hydrochloride or 2- cyclohexen-l-ylarnine hydrochloride, 175.90 g. of lactose and the alcoholic solution of 10 g. of stearic acid. After drying, the granulate is mixed with 56.60 g. of colloidal silicon dioxide, 165 g. of talcum, 20 g. of potato starch and 2.50 g. of magnesium stearate and the mixture is pressed into 10,000 dragee cores. These are then coated with a concentrated syrup made from 502.28 g. of crystallised saccharose, 6.0 g. of shellac, 10.0 g. of gum arabic, 0.22 g. of dyestulf and 1.5 g. of titanium dioxide and dried. The dragees obtained each weigh 120 mg. and contain 25 mg. of active substance.

Example 6 T o produce 1,000 capsules each containing 100 mg. of active substance, 100 g. of active substance, e.g. 3-cyclohexen-l-ylamine salicylate or 2-cyclohexen-1-ylamine hydrochloride are mixed with 173.0 g. of lactose. The mixture is evenly moistened with an aqueous solution of 2.0 g. of gelatine and then granulated through a suitable sieve (e.g. sieve III according to Ph. Helv. V). The granulate is mixed with 10.0 g. of dried maize starch and 15 g. of talcum and the mixture is evenly filled into 1,000 hard gelatine capsules, size 1.

Example 7 A suppository filling is prepared from 10.0 g. of active substance, e.g. 3-cyclohexen-1-ylamine hydrochloride or 2-cyclohexen-1-ylamine salicylate and 160 g. of adeps solidus. 100 suppositories are filled with this mass. Each contains 100 mg. of active substance.

Example 8 5.0 g. of 3-cyclohexen-l-ylamine hydrochloride are dissolved in distilled water up to a volume of 100 ml. This solution is used to fill ampoules, each of 1 ml. or of 2 ml. and containing 50 mg. or 100 mg, respectively, of active substance.

Example 9 500.0 g. of active substance, e.g. 250.0 g. of 3-cyclohexen-l-ylamine salicylate and 250.0 g. of 2-cyclohexenl-ylamine salicylate are mixed with 550.0 g. of lactose and 292.0 g. of potato starch. The mixture is moistened with an alcoholic solution of 8.0 g. of gelatine and granulated through a sieve. After drying, 60.0 g. of potato starch, 60.0 g. of talcum, 10.0 g. of magnesium stearate and 20 g. of colloidal silicon dioxide are mixed in and the mixture is pressed into 10,000 tablets each Weighing 150 mg. and containing 50 mg. of active substance. If desired, the tablets can be grooved for better adaptation of the dosage.

Example 10 A suppository filling is prepared from 10.0 g. of active substance, e.g. 5.0 g. of 3-cyclohexen-1-ylamine hydrochloride and 5 .0 g. of 2-cyclohexen-1-ylamine hydrochloride and 160 g. of adeps solidus. 100 suppositories are filled with this mass. Each contains 100 mg. of active substance.

It is, of course, possible to replace the hydrochlorides and salicylates used in the above examples describing the production of dosage unit forms by the same amounts of a salt of the active substances with another of the acids mentioned above.

What is claimed is:

1. An analgesic composition in the form of a tablet, dragee, capsule, suppository, rectal capsules or ampoules consisting essentially of:

(1) an analgesically effective amount of at least one compound selected from the group consisting of 2- cyclohexen-l-ylamine, 3-cyclohexen-1-ylamine and the pharmaceutically acceptable acid addition salts thereof, and

(2) a pharmaceutical carrier.

2. A therapeutic composition as defined in claim 1 wherein said compound is 2-cyclohexen-1-ylamine hydrochloride.

3. A therapeutic composition as defined in claim 1 wlherein said compound is 2-cyclohexen-1-ylamine salicy ate.

4. A therapeutic composition as defined in claim 1 wherein said compound is 3-cyclohexen-1-ylamine hydrochloride.

5. A therapeutic composition as defined in claim 1 vsiherein said compound is 3-cyclohexen-1-ylamine salicy ate.

6. A method for the treatment of pain which comprises administering to a mammal requiring such treatment an effective amount of at least one compound selected from the group consisting of 2-cyclohexen-1-ylamine, 3-cyclohexen-l-ylamine and the pharmaceutically acceptable acid addition salts thereof, in combination with a pharmaceutical carrier.

7. A method as defined in claim 6 wherein said compound is 2-cyclohexen-1-ylamine hydrochloride.

8. A method as defined in claim 6 wherein said compound is 2-cyclohexen-1-ylamine salicylate.

9. A method as defined in claim 6 wherein said compound is 3-cyclohexen-l-ylamine hydrochloride.

10. A method as defined in claim 6 wherein said compound is 3-cyclohexen-l-ylamine salicylate.

References Cited Chem. Abst. 53, Subject Index A-I, p. 8618 (1959). Chem. Abst. 63, pp. 1797517976 (1965).

ALBERT T. MEYERS, Primary Examiner S. J. FRIEDMAN, Assistant Examiner 

